| Summary: | Alzheimer’s disease (AD) is a complex, age-related neurodegenerative disease that is the most common form of dementia. However, the cure for AD has not yet been founded. The accumulation of amyloid beta (Aβ) is considered to be a hallmark of AD. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), also known as beta secretase is the initiating enzyme in the amyloidogenic pathway. Blocking BACE1 could reduce the amount of Aβ, but this would also prohibit the other functions of BACE1 in brain physiological activity. SPONDIN1 (SPON1) is known to bind to the BACE1 binding site of the amyloid precursor protein (APP) and blocks the initiating amyloidogenesis. Here, we show the effect of <i>SPON1</i> in Aβ reduction in vitro in neural cells and in an in vivo AD mouse model. We engineered mouse induced neural stem cells (iNSCs) to express <i>Spon1</i>. iNSCs harboring mouse <i>Spon1</i> secreted SPON1 protein and reduced the quantity of Aβ when co-cultured with Aβ-secreting Neuro 2a cells. The human <i>SPON1</i> gene itself also reduced Aβ in HEK 293T cells expressing the human <i>APP</i> transgene with AD-linked mutations through lentiviral-mediated delivery. We also demonstrated that injecting <i>SPON1</i> reduced the amount of Aβ and ameliorated cognitive dysfunction and memory impairment in 5xFAD mice expressing human <i>APP</i> and <i>PSEN1</i> transgenes with five AD-linked mutations.
|
|---|
